microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance
Mai Fujiwara, … , Howard L. Weiner, Gopal Murugaiyan
Mai Fujiwara, … , Howard L. Weiner, Gopal Murugaiyan
Published March 17, 2022
Citation Information: J Clin Invest. 2022;132(10):e155693. https://doi.org/10.1172/JCI155693.
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Research Article Autoimmunity Inflammation

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance

Abstract

A disequilibrium between immunosuppressive Tregs and inflammatory IL-17–producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. miR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell–intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg responses and dampening inflammatory T cell responses. Analogous to our findings in mice, miR-92a was elevated in CD4+ T cells from patients with MS, and miR-92a silencing in patients’ T cells promoted Treg development but limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.

Authors

Mai Fujiwara, Radhika Raheja, Lucien P. Garo, Amrendra K. Ajay, Ryoko Kadowaki-Saga, Sukrut H. Karandikar, Galina Gabriely, Rajesh Krishnan, Vanessa Beynon, Anu Paul, Amee Patel, Shrishti Saxena, Dan Hu, Brian C. Healy, Tanuja Chitnis, Roopali Gandhi, Howard L. Weiner, Gopal Murugaiyan

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Figure 4

miR-92a promotes Treg acquisition of an inflammatory phenotype and impairs suppressive function.

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miR-92a promotes Treg acquisition of an inflammatory phenotype and impai...
(A and B) Naive CD4+ T cells from Foxp3gfp and Mir92a–/– Foxp3gfp mice were differentiated in vitro into Tregs and sorted for GFP+ cells, followed by culturing with IL-2 and IL-1β/IL-6/IL-23 (A) or with IL-2 and IL-12/IL-6 (B) for 24, 48, and 72 hours. Representative flow cytometric plots and frequencies of IL-17A+ cells (A) and IFN-γ+ cells (B) are shown (n = 4). (C and D) Representative flow cytometric plots and frequencies of IL-17A+ Tregs (C) and IFN-γ+ Tregs (D) from the spleens of Foxp3gfp and Mir92a–/– Foxp3gfp mice at EAE onset (n = 9–10). (E and F) Foxp3gfp and Mir92a–/– Foxp3gfp mice were immunized with MOG35–55/CFA, and then GFP+ Tregs from dLNs and spleens were sorted at EAE onset and cocultured with CTV-labeled WT CD45.1+ naive CD4+ Tresp cells and APCs. Representative flow cytometric plots (E) and frequencies (F) of CTV-labeled WT Tresp cells at the indicated Treg/Tresp ratios (n = 3–4). (G) Percentage of suppression calculated for the Foxp3gfp and Mir92a–/– Foxp3gfp Tregs in F. (H and I) Naive CD4+ T cells from Foxp3gfp mice were differentiated into Tregs and then sorted for GFP+ cells, followed by culturing with IL-2 alone or IL-2 plus either IL-1β/IL-6/IL-23 (IL-2/Th17) (H) or IL-6/IL-12 (IL-2/Th1) (I) for 24 hours. qPCR analyses of miR-92a (left) and Foxo1 (right) are shown (n = 4–5). Data are representative of 2–3 independent experiments and indicate the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test (C, D, H, and I) or 1-way ANOVA with Šidák’s multiple-comparison test between WT and Mir92a–/– mice within each condition (A, B, F, and G).